The objective of our laboratory is to understand the molecular determinants of cellular survival that allow tumor cells to escape programmed cell death (apoptosis) when they are exposed to chemotherapy or irradiation. Identifying specific molecules that promote survival will provide new, attractive targets for the development of compounds that abrogate survival signals and enhance therapeutic effectiveness. Cellular survival is determined by factors both within the cell and outside the cell, including the contribution of extracellular influences such as soluble growth factors and extracellular matrix molecules. Both growth factors and extracellular matrix molecules stimulate survival through activation of enzymatic pathways within the cell that involve proteins that either add phosphate to downstream substrates (kinase) or remove phosphate (phosphatases). The best described survival pathways depend on activity from kinases such as P13K, Akt, PKC, and MAPK, that become activated when they themselves are phosphorylated. Activation can occur after binding of extracellular growth factors to their cognate receptors, or in the case of some tumor cells, activation is independent of extracellular growth factors and is constitutive. Recently, we have described a role for three signaling pathways that contribute to the survival and therapeutic resistance of lung cancer cells: the PI3K/Akt pathway, the MEK/ERK pathway, and pathways involving isoforms of PKC. Because lung cancer cells appear to be most dependent upon the Akt pathway, we have focused in the last year on this pathway. Four separate studies from our group have highlighted the importance of the PI3K/Akt/mTOR pathway. First, tobacco components activate the pathway in two types of normal human lung epithelial cells, which causes an Akt-dependent, partially transformed phenotype. Second, lung lesions induced by a tobacco carcinogen, NNK, are characterized by progressive activation of the Akt pathway. Third, most lung cancer cells have constitutively activated Akt, which promotes resistance to chemotherapy and radiation. Fourth, Akt activation has prognostic significance for patients with NSCLC. We found that Akt activation is selective for NSCLC tumors vs. surrounding normal lung tissue and confers a poor prognosis for all NSCLC patients, but especially for those with early stage disease. This observation is highly important because most asymptomatic patients who are diagnosed through screening will have early stage disease. In 2007, we performed a series of studies in mice to show that mTOR activity is required for tobacco-carcinogen induced lung tumors. We demonstrated this by inducing lung tumors with NNK in the absence or presence of rapamycin, an FDA-approved immunosuppressant that inhibits mTOR. Rapamycin decreased tumor multiplicity by over 90% and tumor size by over 80%. This was accomplished using physiologically relevant doses of rapamycin. Subsequently, we have shown that inhibition of NNK-tumorigenesis requires depletion of lung-associated Foxp3+ cells. Foxp3+ cells are immunosuppressive, and inhibit the ability of the immune system to eliminate tumors. Thus, these studies link inhibition of the PI3K/Akt/mTOR pathway with elimination of a permissive environment that would allow lung tumors to grow without attack by the innate immune system.